Defecation is a physiological action essential to human life. Dysfunction in defecation causes symptoms of constipation and significantly reduces QOL. Constipation is a generic term for symptoms of defecation trouble associated not only with decreased frequency and/or amount of defecation, but also with changed condition of stool, incomplete evacuation and hypogastric flatulence. Constipation is caused by a variety of factors, including lack of food intake and exercise. In addition to these factors, every year there is an increasing number of constipation cases caused by other factors, for example, constipation associated with aging and social stress, analgesic-induced constipation caused by, e.g., morphine used in cancer treatment and surgical operation, and functional constipation (e.g., constipation associated with irritable bowel syndrome, atonic constipation, rectal constipation, chronic constipation). To treat these types of constipation, patients usually receive education on lifestyle habits to do with diet and exercise along with a laxative for medical treatment. However, a laxative is associated with a problem of frequent diarrhea and/or abdominal pain as side effects although treatment with a laxative may produce a transient improvement in symptoms. In patients with chronic constipation, continuous medication is desired because the symptoms become worse immediately upon interruption of medication; but a laxative is more likely to induce drug resistance in a patient with continuous medication and it may eventually lose its efficacy.
In addition to a laxative, a gastroprokinetic agent such as cisapride may be used for treating constipation. Such an agent is considered to relieve constipation through enhancement of colonic motility. However, agents of this type have serious side effects including neurological effects, as represented by the fact that cisapride was withdrawn from the market because it was suspected to cause sudden death due to QT prolongation.
As a strategy to avoid these side effects, gastrointestinal motility may be enhanced through receptors expressed exclusively in the gastrointestinal tract. The motilin receptor is a receptor for gastrointestinal motility hormone and this receptor is considered to be specifically distributed in the gastrointestinal tract. Motilin is known as a gastrointestinal motility hormone that is highly specific to the gastrointestinal tract. It is supposed that motilin stimulates upper gastrointestinal motility in human (see, e.g., Itoh Z. Motilin and clinical application. Peptides. 1997 18:593-608) and also reported not to affect colonic motility (Bradette M, Poitras P, Boivin M. Effect of motilin and erythromycin on the motor activity of the human colon. J Gastrointest Mot 1993 5:247-251). In addition, recent studies suggest the probability that motilin makes an indirect contribution to colonic motility in view of the fact that motilin stimulates acetylcholine-induced colonic contraction; but it is reported that motilin has no direct stimulatory effect on colonic contraction (Chieppa D M, Mansi G, Rinaldi R, Serio M, Nacci C, Montagnani M, Potenza M A, De Salvia M A, Mitolo C I, Rinaldi M, Altomare D F. Effects of erythromycin on human colonic circular muscle in idiopathic chronic constipation. Eur J Clin Invest. 2000 30:66-71). It is therefore unclear whether defecation can be accelerated by motilin or a motilin agonist. It is also reported that erythromycin, a motilin agonist, fails to enhance colonic motility (Jameson J S, Rogers J, Misiewicz J J, Raimundo A H, Henry M M, Oral or intravenous erythromycin has no effect on human distal colonic motility. Aliment Pharmacol Ther. 1992 6:589-95). On the other hand, it is reported that erythromycin relieves constipation (Sharma S S, Bhargava N, Mathur S C. Effect of oral erythromycin on colonic transit in patients with idiopathic constipation. A pilot study. Dig Dis Sci. 1995 40:2446-9). However, it is considered that the relief of constipation may be due to a synergistic effect between indirect enhancement of colonic motility and changes in enterobacterial flora induced by the antibacterial action of erythromycin; and hence, it is unclear whether constipation is relieved by a motilin agonist having a weak or no antibacterial action. In addition, because of its antibacterial action, erythromycin is clinically unsuitable for continuous medication as a therapeutic agent for constipation. Furthermore, in clinical studies, there is no report about an acceleratory effect on defecation by administration of motilin (see, e.g., Kamerling I M, van Haarst A D, Burggraaf J, de Kam M, Biemond I, Jones R, Cohen A F, Masclee A A. Exogenous motilin affects postprandial proximal gastric motor function and visceral sensation. Dig Dis Sci. 2002 47:1732-6; Kamerling I M, Van Haarst A D, Burggraaf J, Schoemaker H C, Biemond I, Jones R, Cohen A F, Masclee A A. Dose-related effects of motilin on proximal gastrointestinal motility. Aliment Pharmacol Ther. 2002 16:129-35; Luiking Y C, Peeters T L, Stolk M F, Nieuwenhuijs V B, Portincasa P, Depoortere I, van Berge Henegouwen G P, Akkermans L M. Motilin induces gall bladder emptying and antral contractions in the fasted state in humans. Gut. 1998 42:830-5).
Based on the above background, there is a need to develop a medicament that improves defecation functions by a different mechanism than a laxative, particularly relieves senile constipation, analgesic-induced constipation (e.g., morphine-induced constipation), and functional constipation (e.g., constipation associated with irritable bowel syndrome, atonic constipation, rectal constipation, chronic constipation). Since a laxative causes a large change in stool condition, it would give a great distress to patients and would not be effective for continuous medication. Also, it is reported that in patients with such constipation, existing agents including a laxative will not always lead to desired clinical effects such as improved QOL (Harari D, Gurwitz J H, Avorn J, Choodnovskiy I, Minaker K L. Correlates of regular laxative use by frail elderly persons. Am J Med. 1995 99:513-8; Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001 182:11S-18S; Thorpe D M. Management of opioid-induced constipation. Curr Pain Headache Rep. 2001 5:237-40; Alaradi O, Barkin J S. Irritable bowel syndrome: update on pathogenesis and management. Med Princ Pract. 2002 11:2-17). Under the circumstances, there is a need to provide an agent that facilitates normal defecation without changing stool condition and that continuously improves defecation functions.
On the other hand, JP 6-56843 A and W093/24509 teach that a specific type of erythromycin derivative serves as a motilin agonist and enhances upper gastrointestinal motility. Moreover, among this type of compound, erythromycin, 8,9-didehydro-N-demethyl-9-deoxo-6,11-dideoxy-6,9-epoxy-12-O-methyl N-(1-methylethyl)-11-oxo-,(2E)-2-butenedioate (2:1) [development code: GM-611 (Chugai Pharmaceutical Co., Ltd.), hereinafter simply referred to as “GM-611”] is reported to have a weaker antibacterial action than erythromycin and hence suggested to be available for long-term clinical use (Koga H, Takanashi H, Itoh Z, Omura S. Design, SAR and pharmacology of GM-611, the first acid-stable nonpeptide motilin receptor agonist. Drugs Future. 2002 27:255-272). However, it is not known that these compounds have an improving effect on defecation functions, such as those leading to increased frequency and amount of defecation. Thus, as stated above, there is a need to provide a therapeutic and/or preventive agent for defecation dysfunction, which is suitable for continuous medication and acts by a different mechanism than a laxative.